Solid-nanoemulsion preconcentrate for oral delivery of paclitaxel: formulation design, biodistribution, and γ scintigraphy imaging.

Javed Ahmad,Saima Amin,Krishna Chuttani,Anil K Mishra,Kanchan Kohli,Showkat R Mir,A K Panda

doi:10.1155/2014/984756

Abstract

Aim of present study was to develop a solid nanoemulsion preconcentrate of paclitaxel (PAC) using oil [propylene glycol monocaprylate/glycerol monooleate, 4 : 1 w/w], surfactant [polyoxyethylene 20 sorbitan monooleate/polyoxyl 15 hydroxystearate, 1 : 1 w/w], and cosurfactant [diethylene glycol monoethyl ether/polyethylene glycol 300, 1 : 1 w/w] to form stable nanocarrier. The prepared formulation was characterized for droplet size, polydispersity index, and zeta potential. Transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to assess surface morphology and drug encapsulation and its integrity. Cumulative drug release of prepared formulation through dialysis bag and permeability coefficient through everted gut sac were found to be remarkably higher than the pure drug suspension and commercial intravenous product (Intaxel), respectively. Solid nanoemulsion preconcentrate of PAC exhibited strong inhibitory effect on proliferation of MCF-7 cells in MTT assay. In vivo systemic exposure of prepared formulation through oral administration was comparable to that of Intaxel in γ scintigraphy imaging. Our findings suggest that the prepared solid nanoemulsion preconcentrate can be used as an effective oral solid dosage form to improve dissolution and bioavailability of PAC.

Highlights

Oral administration of cancer therapeutics is attractive because of ease of administration to patients, but these molecules have poor oral bioavailability due to variable absorption and high drug effluxing through P-glycoprotein (P-gp) transporters in the lumen [1,2,3]
Paclitaxel (PAC) is one of the most potent chemotherapeutics. It is effective against wide spectrum of cancers such as ovarian cancer, breast cancer, head/neck cancer, and small and non-small cell lung cancers [4, 5]
The poor oral bioavailability is attributed to its significant first-pass metabolism by cytochrome P450 and Pgp mediated effluxing by intestinal cells [7]

Summary

Introduction

Oral administration of cancer therapeutics is attractive because of ease of administration to patients, but these molecules have poor oral bioavailability due to variable absorption and high drug effluxing through P-glycoprotein (P-gp) transporters in the lumen [1,2,3]. Paclitaxel (PAC) is one of the most potent chemotherapeutics. It is effective against wide spectrum of cancers such as ovarian cancer, breast cancer, head/neck cancer, and small and non-small cell lung cancers [4, 5]. Its systemic bioavailability is less than 8% due to low aqueous solubility (0.3 ± 0.02 μg/mL) [3, 6,7,8]. The low solubility is due to its highly lipophilic nature (log P 3.96) and bulky polycyclic structure (molecular weight 853 Da) [3]. The poor oral bioavailability is attributed to its significant first-pass metabolism by cytochrome P450 and Pgp mediated effluxing by intestinal cells [7]. Several formulation approaches including lipid-based nanocarriers [9, 10], prodrug [11], solid dispersions [12], polymeric nanoparticles [13], complexation with cyclodextrin [14], and pretreatment with P-gp inhibitors [15, 16] have been attempted to improve its in vivo and physicochemical properties but still its systemic exposure has not been increased

Methods

Results

Conclusion